The candidate, Lili A. Barouch, M.D., is completing her training in cardiovascular disease and heart failure/transplant at the Johns Hopkins University School of Medicine. As of July 1, 2003, she will be Instructor of Medicine in the Division of Cardiology at Johns Hopkins. Johns Hopkins provides a highly academic environment for young faculty, with extensive physical and intellectual resources to ensure their success. Dr. Barouch's mentor, Dr. Joshua Hare, has a long track record of successful mentorship and productive research in nitric oxide and cardiovascular physiology. Dr. Barouch's long-term goal is to become an independent clinician-scientist in translational research, focusing on the neurohumoral mechanisms of cardiac hypertrophy and ultimately how these mechanisms can be applied to the treatment of clinical manifestations of hypertrophy and heart failure. To achieve this goal, the candidate has developed a research career development plan that includes formal coursework, mentored research, and professional skills essential to embark on a successful career as an independent investigator. Obesity is one of the most common causes of left ventricular hypertrophy, which represents an independent risk factor for congestive heart failure. Leptin, the ob gene product, is a hormone that regulates energy balance and adipose stores while also exerting cardiovascular activity. Hyperleptinemia and leptin resistance are associated with obesity-related hypertension, vascular endothelial dysfunction, and chronic congestive heart failure. In preliminary data contained within this grant, the applicant has shown that leptin possesses anti-hypertrophic properties. Accordingly, the long-term objective of this proposal is to define the mechanisms by which leptin signaling modulates left ventricular hypertrophy. In Aim 1, the applicant will identify the gender-specific effects of disrupted leptin signaling on cardiac structure and function, including the effects of estrogen and any impact on animal survival. Aim 2 will dissect the exact role that nitric oxide plays in myocardial leptin signaling, including its relation to the beta-adrenergic system. Aim 3 will precisely define the role of the beta3-adrenergic receptor in cardiac leptin signaling. The central thesis of this proposal is that disruption of the leptin signaling pathway is a novel mechanism responsible for obesity-associated cardiac hypertrophy. The logical progression of experiments proposed will systematically evaluate and define each step of the hypothesized mechanism. This work has significance for further understanding the development of human cardiac hypertrophy and heart failure. This proposal and career development plan will provide the resources, supportive environment, mentorship, and academic foundation on which Dr. Barouch will launch a successful career as an independent physician-scientist.